Inflammation is a normal response of the organism to infection, injury, and trauma. In this framework, inflammation can be viewed as a complicated series of local immune responses that serve to deal with a threat to the cellular microenvironment. Such reactions are initiated to neutralize invading pathogens, repair injured tissues, and promote wound healing to restore tissue homeostasis. A significant contributions from neuroinflammatory responses have been implied in various neurodegenerative diseases such as Parkinsons Disease, Alzheimers Disease, and Huntington Disease, HIV, as well as brain injury including trauma and stroke. More recent evidence suggests that brain injury as a result of environmental chemical exposure such as heavy metals and pesticides indicates an inflammatory component (Kraft and Harry, 2011). For each of these conditions, identifying and characterizing the neuroprotective versus the injurious aspects of the response still remains a major illusive question. While neuroinflammation has been considered a mediator of secondary damage, the local immune response also has beneficial effects on the traumatized tissue. Microglia serve as the resident mononuclear phagocytes of the brain and are highly heterogeneous within the healthy CNS. They comprise only 10% of the total cell population of the brain; yet, they have multiple morphological and potential functional profiles depending on their environment. Characterization of functional differences between the various microglia structural phenotypes continues to be a major question in addressing the functional role of these cells. One limitation has been with the lack of a good model system where the brain macrophage response is limited to resident microglia and does not involve infiltrating macrophages. This has also served as a limitation in both understanding the role of a brain macrophage response in neurodegenerative disease and developing successful therapeutic approaches. We have established such a model in the mouse by utilizing a known neurotoxicant, the organometal, trimethyltin (TMT), to create focal sites of injury in the absence of an altered blood brain barrier and infiltration of blood borne cells. Using this model we are able to examine the role of microglia in the cell death and clearance of dentate granule neurons as well as their role in promoting survival of hippocampal pyramidal neurons. The heterogeneity of microglia and neuronal responses allows us to characterize the unique properties of neuroinflammation that contribute to neuronal death and neuronal survival. For comparison, we have examined distinct properties of microglia and inflammatory responses in the brain in models of mild ischemia and HIV (2,3). The identification of such factors would then be beneficial in translating these events to a therapeutic intervention for ischemia/stroke or traumatic brain injury to minimize neuronal loss (2,3,5). Further work demonstrates that environmental agents can induce a response of microglia cells directly, we are interested in determining if these cells represent a general target cell for environmental exposures (1,4). If chemical exposure either serves to aberrantly activate microglia or to change their ability to respond appropriately to events occurring in the brain, this can have a significant effect upon central nervous system functioning. Thus, we are developing models that will allow us to examine these cells within a framework of responding to exposure to environmental agents.